Gap junctions are the relatively large pores which allow free diffusion of ions across biological membranes (Finbow, M. E. et al. (1995) Bioessays 17:247-255). The desmosome (macula adherens) is a major component of the epithelial intracellular gap junctional complex. Desmosomes are intimately involved in the structural and functional integration of adjacent epithelial cells. The desmosome serves as a site of reinforcement of cell-cell adhesion as well as an anchorage point for the intermediate filament (IF) scaffold of the cell. Therefore, the desmosome is integral in epithelial cell and epithelial sheet organization. Detailed morphological, biochemical, and molecular analyses of desmosomal components have led to the identification of, and putative function for, as many as eight desmosomal proteins. These include desmoplakin, plakoglobin, and the transmembrane cadhedrin-like glycoproteins, desmoglein and desmocollin (Ouyang, P. and Sugrue, S. P. (1996) J. Cell. Biol. 135:1027-1042).
A human placental 140 kDa phosphoprotein associated with mature desmosomes, pinin, is localized to the intracellular side of the lateral epithelial cell margins near the cytoplasmic face of the desmosomal complex. Pinin further localizes to the vicinity of the IF convergence onto the desmosomes and is recruited to preformed, morphologically identifiable desmosomes. The conceptual translation product of the cDNA clone contains three unique domains: 1) an acidic domain rich in glutamic acid; 2) a glutamine-proline, glutamine-leucine repeat domain; and 3) a serine-rich domain. The serine-rich domain, flanked by numerous protein kinase recognition motif sites, suggests that the C-terminal region of pinin may serve as a substrate(s) for serine/threonine protein kinase(s). It has been postulated that phosphorylation may play an important role in cell-cell adhesion, and in IF and IF-associated protein assembly and function. Pinin may be involved in the organization and/or stabilization of the more mature or definitive desmosome-IF complex (Ouyang, P. and Sugrue, S. P. (supra)).
Pinin cDNA transfected into a human embryonic kidney cell line resulted in enhanced cell-cell adhesion. Northern blot analysis of pinin indicated tissue-specific variation in mRNA size; genomic analysis revealed the existence of a single gene for pinin, suggesting alternative splicing of mRNA. Western blot of two-dimensional gels revealed the existence of multiple isoforms of pinin with isoelectric point ranging from 5.9 to 6.4 (Ouyang, P. and Sugrue, S. P. (supra)).
A number of clinical pathologies have been associated with desmosome morphogenesis and gap junction formation. Altered desmosome morphogenesis has been observed during wound healing, in the skin from an individual with xeroderma pigmentosum, in biopsy material from patients with Alzheimer's disease, in myocytes from patients with hypertrophic cardiomyopathy, in Hailey-Hailey disease keratinocytes, and in follicular dendritic cells and keratodermas from patients with immunosuppressive disorders (Krawczyk, W. S. and Wilgram, G. F. (1973) J. Ultrastruct. Res. 45:93-101; Plotnick, H. and Lupulescu, A. (1983) J. Am. Acad. Dermatol. 9:876-882; Wegiel, J. and Wisniewski, H. M. (1994) Acta Neuropathol. (Berl.) 87:355-361; Sepp, R. et al. (1996) Heart 76:412-417; Cooley, J. E. et al. (1996) J. Invest. Dermatol. 107:877-881; Imal, Y. and Yamakawa, M. (1996) 46:807-833). In epithelial tissue from patients with a hereditary mucoepithelial dysplasia, desmosomes are apparently localized not to the cell-cell interface, but as aggregates within the cytoplasm (Witkop, C. J. et al. (1979) Am. J. Hum. Genet. 31:414-427).
Cancer cells exhibit anchorage-independence. Transformed cells have abnormal or decreased cell-cell, and/or cell-extracellular matrix attachments. Without anchorage, the transformed cell is allowed to metastasize or grow in new environments. Anchorage tends to inhibit, rather than promote, the proliferation of transformed cells. The presence of rare desmosome type intracellular junctions has been associated with chordomas of the mediatinum and with granular cell basal cell carcinoma (Suster, S. and Moran, C. A. (1995) Hum. Pathol. 26:1354-1362; Mrak, R. E. and Baker, G. F. (1987) J. Cutan. Pathol. 14:37-42).
The discovery of a new human pinin splice variant and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of developmental, vesicle trafficking, neoplastic, and immunological disorders.